Time-of-flight mass spectrometers (TOFMSs) measure the abundance of ions in an analyte as a function of the time required for those ions to travel from an ion source to an ion detector that is located at a fixed distance from the ion source. Ions from the ion source are subjected to a short acceleration pulse by applying a voltage between the ion source and an acceleration electrode. The kinetic energy imparted to an ion is proportional to the charge on that ion and the acceleration voltage. The velocity of the ions after acceleration is determined by the acceleration voltage and the mass-to-charge ratio of the ions. Hence, the time of flight (TOF) between the ion source and the detector is a measure of the mass-to-charge ratio of the ions. The ion detector converts an ion impact to an electrical pulse. The spectrum produced by TOFMSs is the charge received by the ion detector as a function of time measured from the time of the acceleration pulse.
The low abundance and statistical nature of the ion impact response necessitate that the spectra from a large number of single pulses are combined to provide the final spectrum for a sample that is being analyzed. For any given application, there is a maximum TOF of interest. In the following discussion, the reciprocal of this TOF will be referred to as the “reference rate”. If the source is pulsed at a rate less than or equal to the reference rate, all of the ions of interest from any given packet will be detected prior to ions from a subsequent pulse arriving at the ion detector. The reference rate is the fastest rate at which the source can be pulsed without having ions of interest from one pulse reaching the detector at a time after ions from a previous pulse have not yet reached the detector.
The time to acquire a spectrum using the reference rate can be too long for many applications. If the analyte is changing over time, the analysis needs to be completed in a time that is much less than the time the analyte evolves. Even in the case of relatively stable samples, there is a limit to the time available on the TOFMS.
One method for decreasing the time needed to acquire a spectrum utilizes a scheme in which the ion source is pulsed at an average rate much higher than the reference rate. In this system, an ion reaching the ion detector could have resulted from any one of a number of pulses. By randomly varying the interpulse interval, the identity of the pulse giving rise to the ion may be determined with high accuracy.
Denote the ions that arrive from a single ion pulse within the range of allowed times of flight as a “transient”. If the source is pulsed at a rate less than or equal to the reference rate, the transients do not overlap, and hence, the launching pulse corresponding to each detected ion is known, and the TOF is the difference in time between the time of the pulse and the time at which the ion was detected. Processing the data from transients to arrive at TOF values for each ion is then relatively simple; however, the data acquisition rate is limited by the number of ions that can be launched in a packet and the TOF of the slowest ion species of interest.
The number of ions per packet is constrained by the available ion sources. In addition, the ion density must not be so great as to have the ions interacting with each other in a manner that alters the TOF of the individual ions or causes the packet to expand so that ions are lost.
There are applications in which the number of transients per unit time must be increased above the reference rate. For example, experiments in which the sample changes significantly in a time that is less than the time needed to collect sufficient impacts at the reference rate pose significant challenges if the TOFMS is limited to the reference rate.
If the TOFMS is operated at a rate above the reference rate, the transient responses will overlap. In this case, the pulse that gave rise to any given ion hitting the detector is not uniquely known from the time of arrival of the ion at the ion detector. For example, an ion striking the detector could be a fast moving ion from the last pulse or a slow moving ion from an earlier pulse. One method for generating a spectrum from such overlapping frames is disclosed in U.S. Pat. No. 8,080,782. In this method, the launching pulses are provided at variable intervals about some predetermined interval that is much shorter than the reference period. An algorithm that makes use of the random nature of the pulses is then used to generate the TOF spectrum by a method that will be discussed in more detail below. For the purposes of the present discussion, it is sufficient to note that the computational workload presented by this algorithm is significant. As a result, the time needed to actually generate a spectrum is much longer than the time needed to accumulate sufficient detector hits.
In applications in which the final spectrum is all that is required, the computations can be performed “off-line”. Hence, the spectrum acquisition time can be significantly improved as measured by the time needed to acquire the data on the TOFMS and the temporal evolution of rapidly evolving spectra can be more closely followed.
There are applications, however, in which the spectrum, or a reasonable approximation thereof, must be available in a time that is less than the processing time of the algorithm discussed above. Consider an experiment in which the sample that is being analyzed is changing with time in a manner that a component of interest is detected during the course of the experiment. When the component appears, the experimental protocol is to be changed. For example, if the component is detected with a TOFMS, a spectrum having sufficient accuracy to detect the component of interest must be available before the component disappears. In this case, the experiment cannot wait for the off-line processing discussed above. Accordingly, a method for providing a reasonable approximation to the final TOFMS spectrum with a minimal time delay is needed.